Drug Design, Development and Therapy最新文献

Background: Myocardial infarction represents a coronary artery ailment with the highest incidence and fatality rates among cardiovascular conditions. However, effective pharmacological interventions remain elusive. This study seeks to elucidate the molecular mechanisms underlying the effects of Ligusticum wallichii on myocardial infarction through network pharmacology and experimental validation.

Methods: Initially, potential targets of Ligusticum wallichii's active ingredients and myocardial infarction-related targets were retrieved from databases. Subsequently, core targets of Ligusticum wallichii on myocardial infarction were identified via the PPI network analysis and subjected to GO and KEGG pathway enrichment analyses. Molecular docking was employed to validate the binding affinities between the core targets and the bioactive components. The findings from network pharmacology analysis were corroborated through in vitro and in vivo experiments.

Results: Seven active ingredients from Ligusticum wallichii were identified, corresponding to 122 targets. Molecular docking revealed robust binding affinities of Myricanone, Senkyunone, and Sitosterol to key target proteins (EGFR, STAT3, and SRC). In vitro, experiments demonstrated that pretreatment with the active components of Ligusticum wallichii protected myocardial cells from OGD exposure and modulated the expression of their key target genes. In vivo, experiments showed that the active components of Ligusticum wallichii significantly improved myocardial infarction via alleviating myocardial fibrosis and oxidative stress and did not elicit toxic effects in mice.

Conclusion: The collective findings suggest that Ligusticum wallichii shows promising potential for myocardial infarction treatment by regulating key target proteins (EGFR, STAT3, and SRC), which play roles in oxidative stress and myocardial fibrosis.

Purpose: This study aims to explore the mechanism of Yangxuerongjin pill (YXRJP) in the treatment of diabetic peripheral neuropathy (DPN) by network pharmacology and metabolomics technology combined with animal experiments, and to provide scientific basis for the treatment of DPN.

Methods: In this study, network pharmacology analysis was applied to identify the active compounds, core targets and signal pathways, which might be responsible for the effect of DPN. The DPN model was established by high-fat diet combined with streptozotocin (STZ) injection, and the rats were given administration for 12 weeks. The body weight, thermal withdrawal latency (TWL), sciatic motor nerve conduction velocity (MNCV), biochemical indexes, pathological sections of sciatic nerve, oxidative stress factors and the expression levels of neuroprotection-related proteins were detected. Metabolomics technology was used to analyze the potential biomarkers and potential metabolic pathways in DPN treated with YXRJP.

Results: The results of network pharmacology showed that YXRJP could treat DPN through baicalin, β-sitosterol, 7-methoxy-2-methylisoflavone, aloe-emodin and luteolin on insulin resistance, Toll-like receptor (TLR), tumor necrosis factor (TNF) and other signaling pathways. YXRJP can prolong the TWL, increase the MNCV of the sciatic nerve, alleviate the injury of the sciatic nerve, reduce the levels of triglyceride (TG), improve the expression of Insulin-like growth factor 1 (IGF-1) protein in the sciatic nerve, and reduce the expression of protein kinase B (AKT) protein. Metabolomics results showed that the potential metabolic pathways of YXRJP in the treatment of DPN mainly involved amino acid metabolism such as arginine, alanine, aspartic acid, lipid metabolism and nucleotide metabolism.

Conclusion: YXRJP can effectively improve the symptoms of DPN rats and reduce nerve damage. The effects are mainly related to reducing oxidative stress injury, promoting the expression of neuroprotection-related proteins, reducing the expression of inflammation-related proteins, and affecting amino acid metabolism, lipid metabolism, and nucleotide metabolism pathways. Our findings revealed that YXRJP has a good therapeutic potential for DPN, which provides a reference for further studies on YXRJP.

Food-Drug Interaction (FDI) refers to the phenomenon where food affects the pharmacokinetic or pharmacodynamic characteristics of a drug, significantly altering the drug's absorption rate or absorption extent. These Interactions are considered as a primary determinant in influencing the bioavailability of orally administered drugs within the gastrointestinal tract. The impact of food on drug absorption is complex and multifaceted, potentially involving alterations in gastrointestinal physiology, increases in splanchnic blood flow rates, and shifts in the gut microbiota's composition. Up to now, extensive research has focused on the interactions between food composition (such as proteins, fats, and vitamins) and drug absorption. In contrast, the impact of food physical properties (such as viscosity, volume, and pH) has received less attention in drug development. This article reviewed the impact of food properties on oral drug absorption based on a comprehensive literature search, focusing on the influence of food volume and food viscosity. From the perspective of pharmacokinetics, we examined interaction trends between food properties and drugs across different classification based on the Biopharmaceutics Classification System (BCS). In addition, we introduced the practical application of physiologically based pharmacokinetic (PBPK) modeling in predicting oral drug absorption under the influence of food Properties.

Selenium (Se), a critically essential trace element, plays a crucial role in diverse physiological processes within the human body, such as oxidative stress response, inflammation regulation, apoptosis, and lipid metabolism. Organ fibrosis, a pathological condition caused by various factors, has become a significant global health issue. Numerous studies have demonstrated the substantial impact of Se on fibrotic diseases. This review delves into the latest research advancements in Se and Se-related biological agents for alleviating fibrosis in the heart, liver, lungs, and kidneys, detailing their mechanisms of action within fibrotic pathways. Additionally, the article summa-rizes some of the anti-fibrotic drugs currently in clinical trials for the aforementioned organ fibroses.

Purpose: Drug-induced liver injury (DILI) is one of the most common and serious adverse drug reactions related to first-line anti-tuberculosis drugs in pediatric tuberculosis patients. This study aims to develop an automatic machine learning (AutoML) model for predicting the risk of anti-tuberculosis drug-induced liver injury (ATB-DILI) in children.

Methods: A retrospective study was performed on the clinical data and therapeutic drug monitoring (TDM) results of children initially treated for tuberculosis at the affiliated Changsha Central Hospital of University of South China. After the features were screened by univariate risk factor analysis, AutoML technology was used to establish predictive models. The area under the receiver operating characteristic curve (AUC) was used to evaluate model's performance, and then the TreeShap algorithm was employed to interpret the variable contributions.

Results: A total of 184 children were enrolled in this study, of whom 19 (10.33%) developed ATB-DILI. Univariate analysis showed that seven variables were risk factors for ATB-DILI, including the plasma peak concentration (C_max) of rifampicin, body mass index (BMI), alanine aminotransferase, total bilirubin, total bile acids, aspartate aminotransferase and creatinine. Among the numerous predictive models constructed by the "H2O" AutoML platform, the gradient boost machine (GBM) model exhibited the superior performance with AUCs of 0.838 and 0.784 on the training and testing sets, respectively. The TreeShap algorithm showed that C_max of rifampicin and BMI were important features that affect the AutoML model's performance.

Conclusion: The GBM model established by AutoML technology shows high predictive accuracy and interpretability for ATB-DILI in children. The prediction model can assist clinicians to implement timely interventions and mitigation strategies, and formulate personalized medication regimens, thereby minimizing potential harm to high-risk children of ATB-DILI.

Background: Givinostat, a potent histone deacetylase (HDAC) inhibitor, is promising for the treatment of relapsed leukemia and myeloma.

Purpose: This study aimed to develop and verify a quick assay for the measurement of givinostat concentration using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) with eliglustat as the internal standard (IS), establishing a basic pharmacokinetic profile for its pre-clinical application and metabolic stability in vitro.

Methods: Sample preparation was performed via protein precipitation using acetonitrile. The analyte (givinostat) and IS were gradient eluted on a Waters ACQUITY UPLC BEH C18 column (1.7 μm, 2.1 × 50 mm) with 0.1% formic acid (A) and acetonitrile (B) as the mobile-phase system. The multiple reaction monitoring (MRM) in positive ion mode was used to detect the mass transition pairs for givinostat and IS as follows: m/z 422.01→186.11 for givinostat, and m/z 405.40→84.10 for IS, respectively.

Results: In the bioanalytical method, good linearity was observed between 2 and 4000 ng/mL (r ²=0.998). The intra- and inter-day precisions (RSD%) were lower than 15%, with an accuracy (RE%) of 95.8%-108.6%. The recovery exceeded 90%, and the matrix effect was within the range of 98.2%-107.6%. Additionally, this method was successful in evaluating pharmacokinetics in rats after an oral dose of 10 mg/kg givinostat. Finally, in vitro results showed that givinostat had a slow intrinsic clearance (CLint) value of 14.92 μL/min/mg protein with a half-life (t_1/2) value of 92.87 min.

Conclusion: Givinostat was rapidly absorbed and cleared slowly in vivo, and it was confirmed by in vitro experiments. This study provides a potential reference for givinostat in clinical studies.

Purpose: To explore the postoperative opioid-sparing effect and incidence of adverse events of different dosages of intraoperative esketamine administration in patients undergoing laparoscopic gynecological surgery.

Patients and methods: Patients undergoing elective gynecological laparoscopic operation was enrolled and randomly allocated to lower-dose esketamine group, higher-dose esketamine group, or control group. Patients in the two intervention groups received esketamine doses of 0.25 mg/Kg and 0.50 mg/Kg before wound incision. Subsequently, maintenance doses of 0.20 mg/Kg/h and 0.40 mg/Kg/h were administered throughout the procedure, respectively. The control group was given an intravenous injection and a maintenance infusion of normal saline. A patient-controlled analgesia (PCA) intravenous pump containing sufentanil was connected to control postoperative pain. Rescue analgesia was provided with injection of tramadol 100 mg.

Results: In total, 120 subjects were included in data analysis. The 24 hours and 48 hours PCA opioid consumption, 24 hours and 48 hours cumulative opioid in both lower-dose and higher-dose esketamine groups were lower than those in the control group. However, postoperative opioid consumption was comparable between the two intervention groups. No differences were found in extubation time, acute postoperative pain intensity, and incidence of adverse effects among the three groups.

Conclusion: Intraoperative esketamine administration at both low and high doses reduces opioid consumption after gynecological laparoscopic surgery, without increasing the risk of adverse events.

Purpose: Phytosome technology, an advanced lipid-based delivery system, offers a promising solution for enhancing the bioavailability and therapeutic efficacy of secondary metabolites, particularly in cancer treatment. These metabolites, such as flavonoids, terpenoids, and alkaloids, possess significant anticancer potential but are often limited by poor solubility and low absorption. This review aims to investigate how phytosome encapsulation improves the pharmacokinetic profiles and anticancer effectiveness of these bioactive compounds.

Patients and methods: This comprehensive review is based on an analysis of recent literature retrieved from PubMed, Scopus, and ScienceDirect databases. It focuses on findings from preclinical and in vitro studies that examine the pharmacokinetic enhancements provided by phytosome technology when applied to secondary metabolites.

Results: Phytosome-encapsulated secondary metabolites exhibit significantly improved solubility, absorption, distribution, and cellular uptake compared to non-encapsulated forms. This enhanced bioavailability facilitates more effective inhibition of cancer pathways, including NF-κB and PI3K/AKT, leading to increased anticancer efficacy in preclinical models.

Conclusion: Phytosome technology has demonstrated its potential to overcome bioavailability challenges, resulting in safer and more effective therapeutic options for cancer treatment. This review highlights the potential of phytosome-based formulations as a novel approach to anticancer therapy, supporting further development in preclinical, in vitro, and potential clinical applications.

Background: Both intramural myomas and thin endometrium exert a detrimental influence on the outcomes of assisted reproductive technology (ART). The downregulation of gonadotropin releasing hormone agonists (GnRH-a) is regarded as an effective approach to reducing the size of intramural fibroids and enhancing endometrial receptivity. Consequently, we conducted this study to assess whether the GnRH-a combined with hormone replacement therapy (GnRH-a-HRT) can improve reproductive outcomes in frozen embryo transfer cycles for patients with a thin endometrium (≤7 mm) and intramural fibroids.

Methods: This retrospective cohort study encompassed 360 patients who underwent frozen embryo transfer following in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. Patients were stratified into three groups based on the endometrial preparation protocol: the natural cycle (NC) group (n=96), the hormone replacement therapy (HRT) group (n=180), and the GnRH-a-HRT group (n=84). The live birth rate (LBR) was designated as the primary outcome, while clinical pregnancy rate (CPR), miscarriage rate, and ectopic pregnancy rate were classified as secondary outcomes.

Results: The LBR and CPR in the GnRH-a-HRT group were significantly higher than those in both the HRT group and the NC group (both P < 0.0001). A logistic regression model indicated that the LBR was significantly higher in the GnRH-a-HRT group compared to both the HRT group (odds ratio, 0.269; 95% confidence interval, 0.114-0.637; P = 0.003) and the NC group (odds ratio, 0.524; 95% confidence interval, 0.457-0.956; P = 0.023). Subgroup analyses based on the number and dimension of fibroids demonstrate the positive efficacy of the GnRH-a-HRT regimen.

Conclusion: Compared to NC and HRT protocol, improved reproductive outcomes were observed in the GnRH-a-HRT group. These findings provide valuable insights for exploration of the underlying mechanisms by which the GnRH-a-HRT protocol enhances reproductive outcomes in patients of thin endometrium with intramural fibroids.

Introduction: Oxidative stress is an important cause of acetaminophen (APAP)-induced liver injury (AILI). Sakuranetin (Sak) is an antitoxin from the cherry flavonoid plant with good antioxidant effects. However, whether sakuranetine has a protective effect on APAP-induced liver injury is not clear.

Methods: Mouse and HepG2 cell models of APAP injury were used to investigate the effect of sakuranetin on AILI and its mechanism. Serum transaminase levels, histological changes, inflammatory mediators, oxidative stress, ferroptosis-related markers and Nrf2 signaling pathway proteins were analyzed.

Results: Sakuranetin significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as inflammatory factor; increased HepG2 activity and decreased cell death; inhibited ROS production, increased glutathione (GSH) content, expression of Glutathione Peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), and decreased malondialdehyde and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) expression in mice and HepG2 cells after APAP treatment. Further analysis showed that sakuranetin induced the activation of the NFE2 Like BZIP Transcription Factor 2 (Nrf2) signaling pathway in liver tissue and HepG2 cells and promoted the nuclear translocation of Nrf2. Moreover, the hepatoprotective effect of sakuranetin and its inhibitory effect on ferroptosis were significantly attenuated by the Nrf2 inhibitor ML385.

Conclusion: Sakuranetin alleviates AILI by activating the Nrf2 signaling pathway and inhibiting ferroptosis, and sakuranetin may be a potential therapeutic agent for the treatment of AILI.